I have observed that levels of Ia antigens are markedly reduced in the senescent thymus. In light of the central role attributed to thymic major histocompatibility antigens in determining immunological self-non-self discrimination and the specificity of the T cell receptor repertoire, it is likely that loss of Ia antigens within the thymic microenvironment is involved in the decay of T cell function observed in aged mice. Using immunoelectron microscopic techniques I have developed to localize Ia antigens in situ, I will ultrastructurally identify the cells which lose Ia antigens within the senescent thymus and document the relative contributions of epithelial and hematogenous Ia+ cells to the thymic microenvironment during development. I have established thymic epithelium in vitro as a model to study the regulation of Ia antigen expression and have found that: 1) thymic epithelial cells from juvenile mice lose Ia antigens when maintained from in culture, thus resembling senescent thymic epithelium, 2) activated T cell products induce re-expression of Ia antigens when added to cultures of in vitro aged epithelial cells. I propose to define the parameters of in vitro Ia antigen re-expression by thymic epithelial cells in response to this mediator, to characterize the Ia inducing agent(s) in activated T cell/macrophage culture fluids, and to test whether or not the ability to re-express Ia antigens in response to this mediator is lost by senescent epithelial cells. Finally, I intend to test whether or not the syngeneic mixed lymphocyte reaction within the thymus is a physiologic source of epithelial Ia inducing activity and to examine age-related changes in the capacity of thymus cells to produce this mediator. Understanding the regulation of Ia antigen expression within the thymus will advance our knowledge of the thymic role in T cell differentiation and may aid in formulating approaches to retard the decay of T cell function observed in aged laboratory animals and man.